Vision loss and blindness due to retinal cell death is a severe problem. In a 2004 publication, the World Health Organization (WHO) estimated that the global population of blind and visually impaired persons was over 300 million, with almost 10 million in the United States (WHO Bulletin 82 pp 844-851—Global Data on Visual Impairment November, 2004). The major cause of blindness among the elderly in the developed world is age-related macular degeneration (AMD), which is estimated to cause half of all blindness cases in the U.S. AMD gradually destroys sharp central vision, which is needed for activities such as driving and reading. AMD is a varied set of diseases characterized by the presence of soft and hard drusen, altered pigmentation of the retinal pigment epithelium (RPE), RPE atrophy, and choroidal neovascularization (CNV). AMD is usually classified into two forms, namely dry and wet AMD. Dry AMD involves the accumulation of debris and deposits in the outer retina, along with atrophic and hypertrophic changes in the RPE, particularly underlying the central retina. Wet AMD is a pathological process, secondary to angiogenic neovascular changes (e.g., CNV) that occur in about 20% of patients with AMD. It remains unclear whether the two forms (wet and dry) are different manifestations of the same disorder, or distinct diseases with distinct origins and pathology. Recently, treatments for wet AMD have been developed. For example, antibodies against Vascular Endothelial Growth Factor (VEGF) such as AVASTIN® and LUCENTIS® from Genentech (South San Francisco, Calif.) have shown a benefit in treating established AMD in some cases.
In addition to AMD, other retinal disorders have been described. Retinitis pigmentosa (RP) is caused by mutations that compromise rod photoreceptor cells (rods) and lead to their death. Some mutations cause rapid death of rod cells, while others lead to a slow loss of these cells. Regardless of the mechanism, however, a common feature is the loss of the rod photoreceptors. As a result of this loss, patients become unable to see in dim illumination, but retain the ability to read and drive when lighting is sufficient. These remaining activities are mediated by cone photoreceptors, which remain intact until most of the rods have died and then they begin to die. Thus, prevention of both rod and cone photoreceptor cell death is desirable as a method of treating or preventing RP.
Glaucoma is another common blinding illness. It involves the loss of the output neurons of the retina, the ganglion cells. In many cases, this death is accompanied by increased intraocular pressure, while in other cases, the pressure is in the normal range. In all cases, ganglion cells die and blindness is the result.
A variety of mouse models are used to investigate retinal cell death and retinal disorders. In particular, because little rod cell death occurs during normal development, retinal cell survival is commonly investigated in a model of retinal degeneration. Mutations in the rod-specific gene phosphodiesterase 6β (PDE 6 β subunit) causes photoreceptor degeneration in several types of animals as well as humans. In mice, this mutation is also known as the rd1 mutation (Bowes et al. (1990) Nature 347:677; McLaughlin et al. (1993) Nat. Genet. 4:130-4; Rakoczy et al. (2006) Exp. Eye Res. 82(5):741, Epub Dec. 1, 2005). Rd1/rd1 mice are homozygous for a nonsense mutation in exon 7 of the Pde6β gene, which completely disrupts production of the β subunit of rod phosphodiesterase (Carter-Dawson et al., 1978). The rods develop, but then undergo rapid degeneration between postnatal day (P) 12 and P21. Thus, mice harboring the mutation are useful models of retinal cell disorders, particularly with respect to photoreceptor degeneration in rod cells. For example, rd1 mice are used as a model for retinitis pigmentosa (RP) in humans (Komeima et al. (2007) J. Cell Physiol. 213:809). Rd1 mice are also used as models for age-related macular degeneration (AMD). (Rohrer et al. (2007) Exp. Eye Res. 84(1):82, Epub Oct. 25, 2006).
The molecular events underlying blindness remain unclear. Because cell death is an important aspect of blindness, molecules and processes involved in regulating cell survival through control of DNA are under active investigation. A key cell survival mechanism is regulation of gene expression by lysine acetylation of histone proteins. Lysine acetylation is the transfer of an acetyl moiety from acetyl-coenzyme A (CoA) to the ε-amino group of a lysine residue. The acetylation is reversible and is controlled in vivo by the competing actions of acetyltransferases and deacetylases, which remove the acetyl moiety. Early research identified histone proteins as a major substrate for lysine acetylation and subsequent research identified many proteins as substrates for in histone acetylation or histone deacetylases (HDACs). Because histone proteins are involved in regulating gene expression, HDACs have been researched primarily as transcriptional corepressors that catalyze histone deacetylation (Nagy et al., 1997; Strahl and Allis, 2000).
Several classes of HDACs exist (see Yang and Grégoire (2005) Mol. Cell. Biol. 25:2873). The class IIA histone deacetylases, which include HDAC4, -5, -7 and -9, share several features. They bind MEF2 and repress its activity, and they undergo intracellular trafficking between the cytoplasm and nucleus. This trafficking is regulated by signal-induced phosphorylation (Miska et al. (1999) Embo. J. 18:5099). For example, HDAC4 can be phosphorylated by calcium/calmodulin-dependent kinase IV (CaMKIV) (Zhao et al. (2001) J. Biol. Chem. 276:35042). Phosphorylation recruits the phospho-binding protein 14-3-3, and the resulting complex is exported efficiently from the nucleus (Wang and Yang (2001) Mol. Cell. Biol. 21:5992). HDAC4 can subsequently reenter the nucleus after dephosphorylation and dissociation from 14-3-3 (Grozinger and Schreiber (2000) Proc. Natl. Acad. Sci. USA doi 10.1073).
There is a need in the art for therapies to prevent, treat, diagnose and prognose vision loss that results from decreased retinal cell function due to one or more retinal disorders or one or more natural events.